Surgical resection for early stage breast cancer has a high rate of cure but a high rate of positive margins. Screening mammography finds smaller cancers and the majority of breast cancers diagnosed in the United States are not palpable but mammographically detected. The operation to remove these tumors requires pre-operative localization that is most commonly done by inserting a wire under x-ray guidance into the breast lesion. This technique is associated with a 20-40% positive margin rate Objective: The purpose of this application is to robustly validate a technique to employ pre-operative injection of ultra-sound contrast enhancement nanoshells to enable intraoperative detection of breast tumors to lower the occurrence of positive margins and to explore the addition of an ablation technique to the particles. Aim 1: Lifetime of GLP scaled up production Silica Microshells: To study the localization ability of gas filled iron doped silica microshells and the stability of the particlesas an ultrasound contrast agent and localization method for occult breast cancers using GLP produced particles. We will develop methods of measuring quality control and particle reproducibility which is necessary for eventual FDA submission. Furthermore, we will examine the time course until the particles degrade in vivo as well as toxicity in vivo. : Aim 2 : To study the Efficacy of microshells in localization of non-palpable tumors to test the efficacy of localizig breast tumors wire localization vs microparticle alone. We will examine if the microparticles will remain closer to the tumor after 24 hours in a living animal in order to simulate movement of the wire in humans during transport and surgical manipulation to see if the particles will be more accurate in directing surgical resection of tumors. Aim 3. Test efficacy of PFC liquid filled nanoshells for Cavitational and Thermal HIFU. The optimal nanoshells will be investigated for their potential as HIFU agents. We will compare the efficacy of focused ultrasound ablation of a benign breast tumor model with or without silica particles to test whether the addition of silica particles increases cell death and decreases toxicity. Conclusion: Because surgical resection of small early cancers remains so important in local control and prevention of metastases, techniques to improve its efficacy in visualizing and removing tumors completely can have a major impact on breast cancer treatment. This project may be able to decrease positive margins, local recurrence and possible cure of breast cancer. Our group has preliminary experience with this technique as proof of principle but seek funding for robust validation of this technique in order to get ready for an IND application in order to be to perform a phase 1 trial in humans.